Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
  • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D495/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
  • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
  • C07D513/04—Ortho-condensed systems

Definitions

• the invention relates to a process for the preparation of D - (+) - biotin from L-cysteine or L-cystine or L-serine via an optically active (7R) -1H, 3H-imidazo [1,5-c] azole as an intermediate .
• the object of the invention was to provide a new process for the production of optically active D - (+) - biotin, which avoids carrying out a resolution and thus discarding or recycling the undesired enantiomer.
• D - (+) - biotin from the naturally occurring amino acids L-cysteine or L-cystine or L-serine via an optically active (7R) -IH, 3H-imidazo [1,5-c] Azole of the formula I can be prepared as an intermediate in a stereospecific manner without additional racemate separation.
• the radical R 3 is preferably unsubstituted or by one or more, particularly preferably one or two, C 1 -C 4 alkyl and / or C 1 -C 4 alkoxy groups substituted benzyl, in particular unsubstituted benzyl, in addition also C 3 -C 5 alk-2-enyl or C 3 -C 6 trialkylsilyl.
• the substituents are preferably the same, but they can also be different. They are preferably in the 4- and / or 2-position, but they can also be in the 3-, 5- and / or 6-position.
• the invention is in particular a process for the preparation of D - (+) - B iotin of L-cysteine or L-cystine or L-serine via an intermediate product of the formula I, preferred is any of the above in which at least one of said radicals Has meanings.
• the invention furthermore relates to compounds of the formula XI, since they represent valuable intermediates and starting products for a large number of synthesis options for optically active D - (+) - biotin.
• R 1 , R 2 , X and Y have the meaning given and R 3 represents a protective group suitable for a nitrogen atom.
• Preferred compounds of the formula XI are those in which X is sulfur and Y is oxygen.
• the compounds of the formula I are prepared by methods known per se, as described in the literature (for example in standard works such as Houben-Weyl, Methods of Organic Chemistry, Georg-Thieme-Verlag, Stuttgart), namely Reaction conditions as are known and suitable for the reactions mentioned. Use can also be made of variants which are known per se and are not mentioned here in detail.
• the starting materials of the formula II are known or can be prepared from L-cysteine or L-serine by known methods, such as, for example, in Schöberl, Hamm, Chem. Ber. 81 [1948], 210 and Karabinos, Szabo, J. Amer. Chem. Soc. 66 [1944], 649 by reacting the free amino acids or their acid addition salts with an alkali metal or alkaline earth metal cyanate or thiocyanate in a suitable solvent such as water, alcohols or mixtures thereof, preferably at elevated temperature, and the intermediate product obtained in situ cyclized under the action of an acid, for example a mineral acid.
• a suitable solvent such as water, alcohols or mixtures thereof, preferably at elevated temperature
• the reaction of the hydantoins of the formula II with carbonyl compounds of the formula III to the bicycles of the formula IV can be carried out by the processes known and customary for acetalizations, such as, for example, in Houben-Weyl, Methods of Organic Chemistry, Vol. VI / 3, p. 199 , are described.
• the reaction partners are preferably reacted with the addition of a dehydrating agent such as. B.
• an acid such as sulfuric acid, phosphoric acid, hydrogen chloride, p-toluenesulfonic acid, an acid derivative such as phosphorus pentoxide, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, a metal salt such as anhydrous Calcium chloride, copper sulfate, iron (III) chloride, an acidic ion exchanger or molecular sieves.
• the water of reaction formed can also be removed by azeotropic distillation with a suitable solvent such as benzene, toluene, chloroform, dichloromethane.
• Suitable inert solvents are preferably hydrocarbons such as pentane, hexane, cyclohexane, benzene, toluene or xylene, and chlorinated hydrocarbons such as dichloromethane, chloroform or carbon tetrachloride.
• R 3 is, for example, benzyl, 4- Methoxybenzyl, 3,4-dimethoxybenzyl, 4-methylbenzyl, allyl, methallyl, crotyl, methoxymethyl, trimethylsilyl, tert-butyldimethylsilyl or tert-butyldiphenylsilyl.
• This protection Groups are prepared by known methods, such as those found in Mac Omie, Protective Groups in Organic Chemistry, Plenum Press, New York, 1973, by reacting the corresponding reactive halides with the bicycles of the formula IV to give (7R) - 1H, 3H-Imidazo [1,5c] azoles of the formula I, introduced.
• the reaction partners are preferably reacted in a suitable solvent with the addition of a basic reagent.
• suitable solvents are in particular ethers such as diethyl ether, di-n-butyl ether, THF, dioxane or anisole, ketones such as acetone, butanone or cyclohexanone, amides such as DMF or phosphoric acid hexamethyltriamide, hydrocarbons such as benzene, toluene or xylene, halogenated hydrocarbons such as carbon tetrachloride or tetrachlorethylene and sulfoxides such as dimethyl sulfoxide or sulfolane.
• a preferred reaction procedure is the reaction of a bicyclic compound of formula IV with a reactive, the - R 3 bearing compound, preferably in a basic medium, important bases being, in particular alkali metal hydroxides such as sodium or potassium hydroxide, alkali metal carbonates or hydrogen carbonates such as sodium carbonate, sodium hydrogen carbonate , Potassium carbonate or potassium hydrogen carbonate, alkali metal acetates such as sodium or potassium acetate, alkaline earth metal hydroxides such as calcium hydroxide, alkali metal hydrides such as sodium hydride, amides such as sodium amide, lithium diisopropylamide, alcoholates such as sodium methylate, sodium ethylate, lithium ethylate or organic bases such as triethylamine, 4-pyridine, imidazole, lutidine, lutidine, lutidine N, N-dimethylamino) pyridine or quinoline are important.
• alkali metal hydroxides such as sodium or potassium hydroxide
• the reaction temperature is usually between -50 ° C and +250 ° C, preferably between -20 ° C and +80 ° C. At these temperatures, the reactions are usually complete after 15 minutes to 48 hours.
• Azolidines of the formula V can be converted into compounds of the formula IV and, as indicated, into the imidazo [1,5-c] azoles of the formula I using alkali metal or alkaline earth metal cyanates or thiocyanates under the reaction conditions already given for the preparation of compounds of the formula II will.
• Organoisocyanates and isothiocyanates of the formula VI are known or can be prepared by known methods, for example in Houben-Weyl, Methods of Organic Chemistry, Vol. VIII, p. 75 and. IX, p. 773, can be obtained.
• ethers such as diethyl ether, di-n-butyl ether, THF, dioxane or anisole, ketones such as acetone, butanone or cyclohexanone, amides such as DMF or phosphoric acid hexamethyltriamide, hydrocarbons such as benzene, toluene or xylene, halogenated hydrocarbons such as carbon tetrachloride or tetrachlorethylene and sulfoxides such as dimethylsulfoxide Sulfolan.
• Basic solvents such as pyridine, lutidine, collidine, diethylamine or triethylamine and mixtures of these bases with the solvents indicated above are also suitable.
• Suitable water-releasing agents are, for example, acids such as sulfuric acid, hydrogen chloride, toluenesulfonic acid or bases such as sodium or potassium hydroxide. You can work in the presence or absence of an inert solvent at temperatures between about 0 ° C and 150 ° C, preferably between about 20 C ° and 100 ° C; come as a solvent, for. B. water and alcohols such as methanol, ethanol, isopropanol or butanol.
• L-cystine is reacted with an alkali metal or alkaline earth metal cyanate or thiocyanate to give a bishydantoin of the formula VII.
• an alkali metal or alkaline earth metal cyanate or thiocyanate for this purpose, use can be made of the same methods which have already been given for the preparation of the hydantoins of the formula I I , the same or similar reaction conditions being used.
• Suitable reducing agents can be found, for example, in Houben-Weyl, Methods of Organic Chemistry, Vol. 15/1, p. 798.
• Sodium / liquid ammonia, zinc / acid or phosphonium iodide are preferably suitable for the reductive cleavage of the disulfide bond.
• the reduction of the bishydantoins of the formula VII is carried out with an equivalent, in particular with an excess of reducing agent, in a suitable solvent which is matched to the chemical nature of the reagent, such as, for. B. water, liquid ammonia, alcohols such as methanol, ethanol, isopropanol, acids such as hydrochloric acid, sulfuric acid, formic acid, acetic acid, ethers such as diethyl ether, THF or dioxane or mixtures thereof, advantageously at temperatures between about -50 ° C and +150 ° C.
• a suitable solvent which is matched to the chemical nature of the reagent, such as, for. B. water, liquid ammonia, alcohols such as methanol, ethanol, isopropanol, acids such as hydrochloric acid, sulfuric acid, formic acid, acetic acid, ethers such as diethyl ether, THF or dioxane or mixtures thereof, advantageously at temperatures between about
• a particularly advantageous method for cleaving the disulfide bond in the compounds of formula VII is their thiolysis with a suitable mercaptan such as. B. thiophenol, butane-1,4-dithiol or 1,4-dithio-threitol analogous to that in Hase, Walter, Inst. J. Pept. Prot. Res. 5 (1973), 283 Way of working.
• the reaction partners are advantageously reacted in a suitable solvent such as, for. B. aqueous alkali metal hydroxide solutions, chlorinated hydrocarbons or liquid ammonia at temperatures between about -40 ° C and +120 ° C.
• the bishydantoins of the formula VII can furthermore be provided with a protective group of the formula R 3 .
• To prepare these protected bishydantoins of the formula VIII use can be made of the methods already given for the preparation of the compounds of the formula I from the bicycles of the formula IV, the same or similar reaction conditions being used.
• Another process for the preparation of the protected bishydantoins of the formula VIII consists in the reaction of L-cystine with an organoisocyanate or isothiocyanate of the formula VI given in analogy to the preparation of compounds of the formula I from azolidines of the formula V, the same or similar Process operated, as already indicated for the preparation of the compounds of formula I.
• One method for producing D - (+) - biotin from I is to reduce an oxo compound of the formula I to an alcohol of the formula IX. Suitable processes can be found, for example, in Houben-Weyl, Methods of Organic Chemistry, Vol. 4 / lc + 4 / ld.
• the reduction can be carried out, for example, by catalytic hydrogenation at temperatures between about 0 ° C. and about 200 ° C. and pressures between about 1 and 200 bar in an inert solvent, for example an alcohol such as methanol, ethanol or isopropanol, an ether such as tetrahydrofuran (THF) or dioxane, an ester such as ethyl acetate, a carboxylic acid such as acetic acid or a hydrocarbon such as cyclohexane.
• an inert solvent for example an alcohol such as methanol, ethanol or isopropanol, an ether such as tetrahydrofuran (THF) or dioxane, an ester such as ethyl acetate, a carboxylic acid such as acetic acid or a hydrocarbon such as cyclohexane.
• an inert solvent for example an alcohol such as methanol, ethanol or isopropanol, an
• Suitable catalysts are suitably noble metals such as Pt or Pd, which can be used in the form of oxides (for example Pt0 2 , PdO), on a support (for example Pd on carbon, calcium carbonate or strontium carbonate) or in finely divided form.
• Pt or Pd which can be used in the form of oxides (for example Pt0 2 , PdO), on a support (for example Pd on carbon, calcium carbonate or strontium carbonate) or in finely divided form.
• Reductions with complex hydrides such as boranes such as diborane, sodium boranate, lithium cyano-trihydroborate, metal hydrides such as sodium hydride, aluminum hydride, silicon hydrides such as triethylsilane, tributyltin hydride and mixed hydrides such as lithium alanate, sodium alanate, sodium bis (2-methoxy- ethoxy) dihydridoaluminate, potassium boranate or lithium boranate.
• complex hydrides such as boranes such as diborane, sodium boranate, lithium cyano-trihydroborate, metal hydrides such as sodium hydride, aluminum hydride, silicon hydrides such as triethylsilane, tributyltin hydride and mixed hydrides such as lithium alanate, sodium alanate, sodium bis (2-methoxy- ethoxy) dihydridoaluminate, potassium boranate or lithium
• the reaction of the oxo compounds of the formula I with the reducing agents is advantageously carried out in a suitable solvent at temperatures between about -100 ° C. and + 150 °, in particular between about 0 ° and 100 °;
• solvents such as water, alcohols such as methanol, Ethanol, isopropanol, butanol, ethers such as tetrahydrofuran, dioxane, diethyl ether, ethylene glycol dimethyl ether and hydrocarbons such as pentane, cyclohexane, benzene, toluene can be considered.
• R 4- Q which carries the radical R 4 , where R 4 is, for example, alkanoyl such as acetyl, aroyl such as benzoyl, 4-nitrobenzoyl, alkylsulfonyl such as methanesulfonyl, ethanesulfonyl, Trifluoromethanesulfonyl, arylsulfonyl such as phenylsulfonyl, aralkylsulfonyl such as benzylsulfonyl means.
• alkanoyl such as acetyl, aroyl such as benzoyl, 4-nitrobenzoyl, alkylsulfonyl such as methanesulfonyl, ethanesulfonyl, Trifluoromethanesulfonyl, arylsulfonyl such as phenylsulfonyl, aralkylsulfonyl
• R 4 is a radical Azol-M, in which Azol stands for a nitrogen-containing, unsubstituted or substituted and / or condensed five-membered ring, such as, for example, imidazole, 1,2,4-triazole, 1,2,3-triazole, benzotriazole, benzimidazole, pyrazole , 3,5-dimethylpyrazole, indazole, and M means CO, CS, SO, S0 2 , S.
• R 4 is preferably acetyl, imidazol-1-ylcarbonyl, imidazol-1-ylsulfinyl, imidazol-1-ylsulfonyl.
• Q represents halogen, alkoxy, alkanoyloxy or a further azole radical.
• a preferred reaction mode is the reaction of an alcohol of formula IX with a reactive compound bearing the radical R 4 , preferably in a basic medium, organic bases such as triethylamine, pyridine, lutidine, collidine or quinoline being particularly suitable as bases.
• the reaction temperature is ge usually between -50 ° C and +150 ° C, preferably between -20 ° C and +80 ° C. At these temperatures, the reactions are usually complete after 15 minutes to 48 hours.
• the activated esters of the formula X can be reacted with a cyanide, advantageously with a metal cyanide such as sodium cyanide, potassium cyanide or copper cyanide or a cyanosilane such as e.g. Trimethylsilyl cyanide, B-trimethylsilylpropionitrile or diethylaluminium cyanide, e.g. in an inert solvent such as dichloromethane, toluene, pyridine, dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone or hexamethylphosphoric triamide at temperatures between -50 ° C and 200 ° C.
• a metal cyanide such as sodium cyanide, potassium cyanide or copper cyanide
• a cyanosilane such as e.g. Trimethylsilyl cyanide, B-trimethylsilylpropionitrile or diethylaluminium cyanide
• a preferred process for the preparation of nitriles of the formula XI from activated esters of the formula X, in which R 4 is a radical azole-M with the meaning given above, consists in an additional activation of the esters of the formula X by their N-alkylation.
• Suitable alkylating agents for this are, for example, alkyl, alkenyl and aryl iodides, bromides, chlorides, sulfates and sulfonates.
• a suitable solvent such as, for example, ethers such as diethyl ether, tetrahydrofuran, dioxane or ketones such as acetone, diethyl ketone, methyl isobutyl ketone; however, it can also be carried out without the addition of solvents.
• nitriles of the formula XI from esters of the formula X consists in the reaction of the latter with a cyanosilane Methods such as, for example, MT Reetz et al., Tetrahedron 39 (1983) 961; T. Hiyama et al., Synthesis 1986 689 or Houben-Weyl, Vol. E5, pp. 1389 ff (1985).
• the compounds of the formula X in which R 4 is alkanoyl or aroyl, in particular alkanoyl such as acetyl, are particularly suitable for this reaction.
• Trimethylsilyl cyanide proves to be a particularly suitable cyanation reagent.
• the reactants are expediently placed in an inert solvent such as e.g. Dichloromethane or toluene at temperatures from -50 ° C to 150 ° CV, optionally with the addition of a catalyst such as e.g. Tin (IV) chloride, titanium (IV) chloride, tin (IV) triflate or zinc bromide.
• esters of formula X can be isolated and reacted with a cyanide in the manner described above to give the nitriles of formula XI, but they can also be formed in situ without being isolated, formed and reacted with a cyanide.
• Nitriles of the formula XI can be reacted with bases or acids to give the acids of the formula XII in which R 5 is H, the bases being in particular alkali metal hydroxides such as sodium or potassium hydroxide, alkali metal carbonates or hydrogen carbonates such as sodium carbonate, sodium hydrogen carbonate, potassium carbonate or potassium hydrogen carbonate or Alkaline earth metal hydroxides such as calcium hydroxide are suitable.
• suitable acids are hydrochloric acid, sulfuric acid or hydrobromic acid.
• the reaction temperature is usually between -20 ° C and +200 ° C, preferably between 0 ° C and +100 ° C. At these temperatures, the reactions are usually complete between 30 minutes and 48 hours.
• nitriles of the formula XI can be reacted with acid catalysis to give acid derivatives of the formula XII, in which R 5 is lower alkyl, cycloalkyl or aryl.
• Suitable acids are in particular hydrogen chloride, sulfuric acid and boron trifluoride, for example in the form of its diethyl ether adduct.
• the reaction is advantageously carried out in an excess of the alcohol R 5- O H as solvent at temperatures between 0 ° C. and +150 ° C.
• Heavy metal salts such as silver nitrate, mercury (II) chloride or mercury (II) acetate and the subsequent decomposition of the intermediate metal mercaptides with hydrogen sulfide can also be used as cleavage reagent.
• Solvents suitable for this cleavage reaction can be found, for example, among alcohols such as methanol, ethanol, amides such as dimethylformamide or ethers such as tetrahydrofuran.
• Acid derivatives of the formula XII, in which XS is XS, can be reacted with reducing agents to give intermediates of the formula XIIa, in which R 6 is CHR R and XS .
• Suitable reducing agents are, for example, metals such as zinc.
• the acid derivatives are cleaved by reduction with metals, preferably in an acidic environment.
• Suitable acids are, for example, mineral acids such as hydrochloric acid or sulfuric acid or organic acids such as formic acid or acetic acid. These acids are expediently used as solvents or in a mixture with other solvents such as alcohols.
• the reaction temperature is usually between 0 ° C and 200 ° C, preferably between 20 ° C and 150 ° C. At these temperatures, the reactions are usually completed between 15 minutes and 24 hours.
• the intermediates of formula XIIa obtained can be isolated; however, they are expediently reacted in situ to give the known lactones of the formula XIII.
• the latter lactones are often already formed to a high or complete extent when the bicycles of the formula XII are cleaved.
• Suitable agents for this purpose are, for example, in alkali metal salts such as potassium or sodium acetate, potassium thioacetate, in acids such as methanesulphonic acid, p-toluenesulphonic acid, phosphoric acid, sulfuric acid or hydrochloric acid, in anhydrides such as acetic anhydride or trifluoroacetic anhydride or in other dehydrating reagents or dicidicyclic acid, such as aluminum oxide, potassium hydroxide, for example alumina cyanide carboxylate, such as aluminum oxide, potassium oxide, for example, alumina cyanide carboxylate Available.
• lactonizing agents often proves to be advantageous.
• Suitable reaction conditions for lactonization can be found, for example, in Houben-Weyl, Methods of Organic Chemistry, volume E5.
• nitriles of the formula XI are converted to oxo compounds of the formula XIV with an organometallic compound implemented.
• organometallic compounds are, for example, those of magnesium (Blaise process), zinc (Reformatzky process), lithium or aluminum.
• the reaction conditions for converting the organometallic compounds are based on the nature and chemical reactivity of the functional groups present and can be selected analogously to known processes, as described, for example, in Houben-Weyl, Methods of Organic Chemistry, Vol. VII / 2a, p. 603, are described.
• Suitable bases for this are, for example, alkali metal hydroxides such as sodium or potassium hydroxide, Alkali metal carbonates such as sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, alkali metal acetates such as sodium or potassium acetate, alkaline earth metal hydroxides and oxides such as calcium hydroxide, calcium oxide or aluminum oxide or organic bases such as triethylamine, pyridine, lutidine, piperidine, morpholine, piperazine, collidine or quinoline.
• Basic ion exchangers are also suitable for the cyclization of compounds of the formula XV.
• the reaction is expediently carried out in an inert solvent.
• Suitable inert solvents are preferably hydrocarbons such as cyclohexane, benzene, toluene, ethers such as tetrahydrofuran, dioxane, amides such as dimethylformamide, hexamethylphosphoric acid triamide, sulfoxides such as dimethyl sulfoxide, alcohols such as methanol, ethanol, esters such as ethyl acetate or lower carboxylic acids such as formic acid or acetic acid.
• An excess of organic base is also suitable as a solvent, which in combination with a lower carboxylic acid is a particularly preferred cyclization medium.
• the reaction temperatures are advantageously between about 0 ° and 200 ° C, preferably between 20 and 150 ° C, the reaction times between about 1 and 48 hours.
• Hemiacetals of the formula XVI are known and can be converted to D - (+) - biotin by known methods, such as, for example, from DE-20 58 234.
• Good results can also be achieved by reacting the nitriles of the formula XI with 2-mercaptoethanol to give the corresponding 2-substituted 1,3-benzooxathiazoles and reducing them using sodium borohydride.
• the reduction of the nitriles of the formula X I takes place particularly advantageously with complex hydrides such as sodium hydro-triethoxyaluminate, lithium hydro-triethoxyalanate or, particularly preferably, with diisobutylaluminium hydride.
• the complex hydrides are advantageously reacted with the nitriles of the formula XI in an inert solvent.
• Suitable inert solvents are preferably hydrocarbons such as pentane, hexane, cyclohexane, benzene or toluene or ethers such as diethyl ether, tetrahydrofuran, dioxane or ethylene glycol dimethyl ether and mixtures of these solvents with one another.
• the reaction temperatures are advantageously between about -120 ° C and +150 ° C, preferably between -80 ° C and +100 ° C, the reaction times between about 30 minutes and 24 hours.
• the unsaturated compounds of the formula XVIII can be prepared from the aldehydes of the formula XVII using suitable phosphororganylenes in the presence of a base.
• phosphoranes can be converted according to the methods described in Houben-Weyl, Methods of Organic Chemistry, Vol. 5/16, p. 383, and phosphonates after formation of the anion in analogy to, for example, in Organic Reactions, Vol. 25, John Wiley, New York, 1978, chap. 2, described method or Phosphine oxides in the manner described, for example, in Houben-Weyl, Methods of Organic Chemistry, Vol. XII / 1, p.
• Suitable bases for preparing a reactive phosphorylide, phosphonate or phosphine oxide anion are, depending on the deprotonation ability of the phosphororganyl used, for example alkali metal hydroxides such as sodium or potassium hydroxide, alkali metal carbonates such as sodium or potassium carbonate, alcoholates such as sodium methylate, sodium ethylate, lithium ethylate or potassium tert.
• alkali metal amides such as potassium or sodium amide
• alkali metal organyls such as methyl lithium, butyllithium or phenyllithium or other organic bases such as lithium diisopropylamide or sodium methylsulfinylmethylide.
• the reaction is expediently carried out in an inert solvent.
• Suitable inert solvents are preferably ethers such as diethyl ether, ethylene glycol dimethyl ether, tetrahydrofuran or dioxane and amides such as dimethylformamide, hexamethylphosphoric acid triamide, dimethyl acetamide or N-methylpyrrolidone, furthermore sulfoxides such as dimethyl sulfoxide or sulfolane and hydrocarbons such as pentane, hexane, cyclohexane or benzene.
• the reaction temperatures are expediently between about -10.degree. C. and about +150.degree. C., preferably between +20.degree. C. and +100.degree. C., depending on the reactivity of the phosphororganyl used, and the reaction times are between 1 and 48 hours.
• oxo compounds of the formula XIV can be converted into biotin derivatives of the formula XX by methods analogous to the cleavage of acid derivatives of the formula XII, where R 3 , X, Y and Z have the meaning given.
• Biotin derivatives of the formula XIX are known and can be prepared by known methods such as e.g. in DE-20 58 234, EP-O 036 030 and EP-O 084 377, to be converted to D - (+) - biotin.
• the process according to the invention thus allows the production of optically active D - (+) - biotin in a simple and stereospecific manner in high yields from easily accessible, inexpensive starting materials in a few synthetic steps, some of which can be carried out in one-pot processes, and thus represents a significant advance in the field of Biotin synthesis.
• the solution is then stirred into 5000 ml of ice water and extracted five times with 500 ml of toluene each.
• the combined organic phases are washed with water and saturated sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure.
• reaction mixture is then stirred into 1000 ml of ice water and extracted three times with 200 ml of toluene.
• the combined organic phases are washed with water and saturated sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure.
• the red reaction mixture is carefully mixed with 0 ml of 1 N hydrochloric acid at 0 ° C and stirred at room temperature until complete decolorization.
• the organic phase is then separated off, washed twice with 1000 ml of water each time, dried over sodium sulfate and concentrated.
• the solution is cooled to room temperature, washed three times with 200 ml of 1N hydrochloric acid and 200 ml of toluene are distilled off.
• reaction mixture is then carefully mixed at 0 ° C. with 350 ml of 1 N hydrochloric acid and stirred at room temperature until it has completely decolorized.
• the organic phase is separated off, washed twice with 300 ml of water each time, dried over sodium sulfate and concentrated.
• the solvent is then largely distilled off, 200 ml of water are added and the mixture is extracted three times with 100 ml of dichloromethane each time.
• the clear solution is stirred for 30 minutes at room temperature, washed twice with 150 ml of water each time, dried over sodium sulfate and filtered.
• the reaction mixture is then stirred into 500 ml of ice water and extracted three times with 150 ml of ethyl acetate each time.
• the combined organic phases are washed with water and saturated sodium chloride solution and concentrated under reduced pressure.
• the hydrolysis of the nitrile obtained is carried out analogously to the manner described in Example 6 using 200 ml of n-butanol, 19.8 g (0.3 mol) of 85% potassium hydroxide and 40 ml of water.
• the mixture is then cooled to 60 ° C., filtered and concentrated under reduced pressure.
• the mixture is then cooled to room temperature, stirred into 900 ml of water and extracted four times with 100 ml of toluene.
• the combined organic phases are washed three times with 50 ml of water and once with 50 ml of saturated saline and concentrated under reduced pressure. The residue is recrystallized from ethyl acetate.
• the mixture is then cooled to room temperature, stirred into 800 ml of water and extracted four times with 100 ml of toluene.
• the combined organic phases are washed three times with 50 ml of water and once with saturated sodium chloride solution and concentrated under reduced pressure.
• the mixture is then cooled to room temperature, stirred into 800 ml of water and extracted four times with 100 ml of toluene.
• the combined organic phases are washed three times with 50 ml of water and once with saturated sodium chloride solution and concentrated under reduced pressure.
• the oily residue is dissolved in 100 ml of dimethylformamide and heated at 130 ° C for 3 hours.
• the mixture is then cooled to room temperature, stirred into 800 ml of water and extracted four times with 100 ml of toluene.
• the combined organic phases are washed three times with 50 ml of water and once with saturated sodium chloride solution and concentrated under reduced pressure.
• the mixture is then cooled to room temperature, washed twice with 25 ml of 1N hydrochloric acid, dried over sodium sulfate and concentrated under reduced pressure.
• the mixture is then cooled to room temperature, stirred in 1500 ml of water, extracted four times with 200 ml of toluene, the combined extracts are washed three times with 150 ml of water and once with saturated sodium chloride solution and concentrated under reduced pressure.
• the mixture is then cooled to room temperature, stirred into 200 ml of water, extracted four times with 100 ml of toluene, the combined extracts are washed three times with 50 ml of water and once with 50 ml of saturated sodium chloride solution and concentrated under reduced pressure.
• a Grignard reagent solution prepared from 3.68 g (30 mmol) of 1-chloro-4-methoxybutane and 0.97 g (40 mmol) of magnesium in 15 ml of tetrahydrofuran is added dropwise at 40 ° C. under nitrogen to a solution of 6.71 g ( 20 mmol) (7R, 7aR) -3-phenyl-6-benzyl-7-cyano-7,7a-dihydro-1H, 3H-imidazo [1,5-c] thiazol-5 (6H) -one in 10 ml Tetrahydrofuran.
• the mixture is stirred at 40 ° C.
• the pale yellow oil is dissolved in 3.66 g (61 mmol) of anhydrous acetic acid at room temperature, 5.19 g (61 mmol) of piperidine is added dropwise with ice cooling and the melt is heated to 100 ° C. for 90 minutes with stirring.
• the mixture is then cooled to 20 ° C., 150 ml of water are added and the mixture is extracted three times with 100 ml each of tert-butyl methyl ether.
• the combined organic phases are washed with 1N hydrochloric acid and water, dried over sodium sulfate and concentrated under reduced pressure.
• the mixture is then stirred at room temperature for one hour, then at 50 ° C. for 2 hours, cooled to 0 ° C. and decomposed with a mixture of 30 ml of ice water and 25 ml of conc. Hydrochloric acid.
• a solution of 12.40 g (66 mmol) 1 is added dropwise at 23 to 27 ° C to a suspension of 5.49 g (226 mmol) of magnesium shavings in a mixture of 35 ml of diethyl ether and 35 ml of toluene, which is stirred under nitrogen , 2-dibromoethane in 18 ml of diethyl ether, stirred for 45 minutes at room temperature and then a solution of 8.38 g (66 mmol) of 1,4-dichlorobutane in a mixture of 18 ml of diethyl ether and 38 ml of toluene is added dropwise within 25 minutes without cooling .
• Carbon dioxide is then passed in for 60 minutes, the temperature being allowed to rise to 0.degree. It is then concentrated under reduced pressure and the residue is partitioned between 150 ml of 1N hydrochloric acid and 200 ml of ethyl acetate. The organic phase is separated off, dried over sodium sulfate and concentrated under reduced pressure.
• the mixture is then cooled to 25 ° C., mixed with 100 ml of water, adjusted to pH 3 with 2 N hydrochloric acid and extracted three times with 50 ml of ethyl acetate each time.
• reaction mixture is then cooled to -30 ° C. and carbon dioxide is passed in for 60 minutes, the temperature being allowed to rise to 0 ° C.
• the crude product is dissolved in 40 ml of methanol, mixed with 30 ml of saturated methanolic hydrochloric acid and the solution is stirred for 2 hours at room temperature. It is then concentrated under reduced pressure and the oily residue is taken up in 100 ml of toluene.
• the phases are separated, washed twice with 100 ml of water each time, dried over sodium sulfate and concentrated under reduced pressure.
• reaction mixture is stirred for 60 minutes at 20 ° C., cooled to 0 ° C. and a solution of 13.54 g (40 mmol) of a mixture of (7R, 7aR) and (7S, 7aR) -2 is dripped within 15 minutes -Oxo-3-phenyl-6-benzyl-7,7a-dihydro-1H, 3H, 6H-imidazo [1,5-c] thiazole-7-carbaldehyde in 50 ml of tetrahydrofuran. After a further 60 minutes, the reaction mixture is stirred into 200 ml of ice water and concentrated with. Hydrochloric acid brought to pH 2.
• the phases are separated and the aqueous phase is extracted twice with 50 ml of ethyl acetate each.
• the combined organic phases are washed with water and saturated sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure.
• the crude product is then chromatographed on silica gel using ethyl acetate.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
• Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)

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• 1987
  • 1987-04-06 EP EP87105054A patent/EP0242686B1/fr not_active Expired - Lifetime
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